Multiple speed process for preserving heat sensitive portions of a thermokinetically melt blended batch

ABSTRACT

The present disclosure is directed to compositions and methods for making a pharmaceutical composition by thermokinetic compounding, wherein the compositions include one or more thermolabile components, for example one or more active pharmaceutical ingredients (API) with one or more pharmaceutically acceptable excipients. The methods comprise thermokinetic processing of the thermolabile components into a composite by blending certain thermolabile components in a thermokinetic mixer using multiple speeds during a single, rotationally continuous operation. The composite can be further processed into pharmaceutical compositions by conventional methods known in the art, such as hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to and claims priority under U.S.Provisional Application Ser. No. 60/957,044, filed on Aug. 21, 2007,U.S. Provisional Application No. 61/050,922, filed on May 6, 2008,application Ser. No. 12/196,154, filed on Aug. 21, 2008, andInternational Patent Application 20 PCT/US2008/073913, entitled“Thermo-Kinetic Mixing for Pharmaceutical Applications,” filed on Aug.21, 2008, and is a continuation of U.S. patent application Ser. No.13/190,176 filed Jul. 25, 2011 entitled “Multiple Speed Process forPreserving Heat Sensitive Portions of a Thermokinetically Melt BlendedBatch”, the entire contents of each of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Field of the Invention

The present disclosure relates in general to the field of pharmaceuticalmanufacturing, and more particularly, to thermokinetic mixing of activepharmaceutical ingredients (APIs) to produce novel dosage forms.

Description of Related Art

Current high-throughput molecular screening methods used by thepharmaceutical industry have resulted in a vast increase in theproportion of newly discovered molecular entities which are poorlywater-soluble. The therapeutic potential of many of these molecules isoften not fully realized either because the molecule is abandoned duringdevelopment due to poor pharmacokinetic profiles, or because ofsuboptimal product performance. Also, in recent years the pharmaceuticalindustry has begun to rely more heavily on formulational methods forimproving drug solubility owing to practical limitations of saltformation and chemical modifications of neutral or weakly acidic/basicdrugs. Consequently, advanced formulation technologies aimed at theenhancement of the dissolution properties of poorly water-soluble drugsare becoming increasingly more important to modern drug delivery.

U.S. Pat. No. 4,789,597, issued to Gupta, is directed to theincorporation of chemically reactive agents on resin particles. Briefly,chemically reactive agents are locked to particles of suitable syntheticresins without wholly fluxing the resins. A high quality intermediateproduct is obtained having no premature reaction taking place, suitablefor further techniques. The process includes the steps of intensivelymixing and thermokinetically heating a batch of finely divided resinparticles, with a chemically reactive agent, in an enclosed mixingchamber with a plurality of blades attached to arms rotating about acentral axis within the chamber, and having a blade tip speed of atleast about 18 meters per second, mixing the batch until the chemicallyreactive agent is locked to the resin particles, ensuring thattemperature of the batch stays well below decomposition temperature ofthe reactive agent and below fluxing temperature of the resin particles,discharging the batch from the mixing chamber and cooling the dischargedbatch to avoid agglomeration of the resin particles.

U.S. Pat. No. 5,895,790, issued to Good, is directed to thermosetting awide range of polymer blends. Briefly, a wide range of polymer blendsand waste thermoset material can be recovered. One method ofthermosetting a wide range polymer blends forms a homogenous andadaptable material. This material has a melt index of zero and arelatively predictable density. Very high levels of fibrous non-polymersmay be added to the first material.

U.S. Pat. No. 6,709,146, issued to Little, is directed to athermokinetic mixer and method of using the mixer. Briefly, athermokinetic mixer has a mixing chamber with shaft projectionsremovable at least in part and replaceable without cutting theprojections from the shaft. In one embodiment, only a tip portion ofsuch projections are removable and replaceable without such cutting. Inanother embodiment, shaft projections into the mixing chamber include atooth having a substantially reticulated face forming a deflectingsurface such that substantially all mixing chamber particlesencountering the tooth strike are deflected at an incident substantiallylateral angle from the deflecting surface.

U.S. Pat. No. 4,764,412, issued to Burns, discloses the use of a highspeed mixer with a heated jacket about its vertical mixing chamber tofirst mix a set of components at 1700 rpm. The high speed mixer isstopped and after additional components are added, the rotational speedof the mixer is increased to 3400 rpm. Operation of the high speed mixerat a rotation speed of 3400 rpm generates heat which is advantageous infurther processing of the mixture.

U.S. patent application Ser. No. 12/196,154, filed by the same inventoras this application and additional co-inventors, is directed to theapplication of thermokinetic compounding in the field of pharmaceuticalmanufacturing. Thermokinetic compounding is a method of thermokineticmixing until melt blended. A pharmaceutical composition or compositemade by thermokinetic compounding may be further processed according tomethods well known to those of skill in the field, including but notlimited to hot melt extrusion, melt granulation, compression molding,tablet compression, capsule filling, film-coating, or injection moldinginto a final product. One embodiment is directed to a method of making apharmaceutical composition that includes one or more activepharmaceutical ingredients with one or more pharmaceutically acceptableexcipients by the thermokinetic compounding process. Another embodimentis directed to the composite comprising one or more APIs with one ormore pharmaceutically acceptable excipients made by thermokineticcompounding is the final product.

Although the application of thermokinetic compounding in the field ofpharmaceutical manufacturing offers significant advantages over othermethodologies known in the pharmaceutical arts, it is possible thatissues can arise in continuously melt blending certain heat sensitive orthermolabile components with certain non-thermolabile components using athermokinetic mixer. Blending such a combination of components oftenrequires using an elevated shaft speed or a reduced shaft speed for anextended processing time sufficient to impart complete amorphosity onthe fully processed batch. In certain cases, this results in anexceedance of a limit temperature or heat input for an unacceptableduration. The batch thus experiences unacceptable degradation of thethermolabile components, as the substantial amount of heat absorbed bythe entire batch results in thermal degradation of thermolabilecomponents instead of increasing overall batch temperature.Substantially complete amorphosity is a measure well-known in the art ofpharmaceutical preparation and processing; bioavailability may besignificantly impaired in compositions lacking substantially completeamorphosity.

BRIEF SUMMARY OF THE INVENTION

The present disclosure unexpectedly solves the issues associated withblending certain heat sensitive or thermolabile components in athermokinetic mixer by using multiple speeds during a single,rotationally continuous operation on a batch containing thermolabilecomponents. Identified herein is a novel thermokinetic mixer and mixingprocess that can blend heat sensitive or thermolabile components whileminimizing any substantial thermal degradation. In particular, thedisclosure is useful in processing mixtures that include thermolabilecomponents whose exposure to a melt temperature or a cumulative heatinput over a defined time period results in substantial degradation. Theresulting pharmaceutical compositions have increased bioavailability andstability. In addition, the methods disclosed herein are easily scalableto commercial production of pharmaceutical compositions.

One embodiment of the present disclosure is a method for continuousblending and melting of an autoheated mixture in the mixing chamber of ahigh speed mixer, where a first speed is changed mid-processing to asecond speed upon achieving a first desired process parameter. Inanother embodiment, the second speed may be maintained until a finalprocess parameter is achieved, whereupon shaft rotation is stopped and amelt blended batch is withdrawn or ejected from the mixing chamber forfurther processing. In another embodiment, one or more intermediatespeed changes may be made to the shaft rotational speed between thesecond speed and stopping the shaft rotation. Process parameters whichdetermine shaft speed changes are predetermined and may be sensed anddisplayed, calculated, inferred, or otherwise established withreasonable certainty so that the speed change(s) are made during asingle, rotationally continuous processing of a batch in a mixingchamber of the high speed mixer. Another embodiment is the use ofvariations in the shape, width and angle of the facial portions of theshaft extensions or projections that intrude into the main processingvolume to control translation of rotational shaft energy delivered tothe extensions or projections into heating energy within particlesimpacting the portions of the extensions or projections.

The present inventor investigated the melt blending of various mixturesincluding thermolabile components in a thermokinetic mixing chamber. Thepresent inventor unexpectedly found that using multiple speeds during asingle, rotationally continuous operation on certain batches containingthermolabile components solved the problem of exceeding a limittemperature or excessive heat input for the batch. The present inventoralso surprisingly found that varying the shape, width and angle awayfrom a shaft axis plane of a shaft extension or projection provided amethod of controlling the shear delivered to a particle, which in turnprovided control over shaft energy translated into heat energy availablefor softening or melting a polymer part of a particle in a thermokineticmixing chamber.

An embodiment of the present disclosure is a method of blending acomposition of two or more ingredients, wherein the ingredients compriseone or more heat sensitive or thermolabile components, wherein theresulting composition is amorphous, homogenous, heterogenous, orheterogeneously homogenous, the method comprising mixing the ingredientsin a thermokinetic mixing chamber, wherein a thermokinetic mixer shaftis operated at a first speed until achieving a predetermined parameter,at which time the shaft speed is adjusted to a second speed for a secondtime period, wherein the mixing process is substantially uninterruptedbetween the first and second time periods. In another embodiment of thepresent disclosure, the thermokinetic mixer shaft is operated at one ormore speeds until achieving a predetermined parameter, at which time theshaft speed is adjusted to a different speed for a different timeperiod, wherein the mixing process is substantially uninterruptedbetween the two or more time periods. An example of such an embodimentis a method of blending a composition of two or more ingredients,wherein a thermokinetic mixer shaft is operated at a first speed untilachieving a predetermined parameter, at which time the shaft speed isadjusted to a second speed for a second time period, wherein the mixingprocess is substantially uninterrupted between the first and second timeperiods, and wherein at the end of the second time period a rotationalspeed of the shaft is changed from the second speed to a third speed fora third time period upon achieving a predetermined parameter. In oneembodiment, the mixing process is substantially uninterrupted betweenthe second and third time periods.

In certain embodiments, the heat sensitive or thermolabile componentsmay comprise one or more active pharmaceutical ingredients, one or morepharmaceutically acceptable excipients, or one or more pharmaceuticallyacceptable heat sensitive polymers. In other embodiments, the heatsensitive or thermolabile components may comprise one or more activepharmaceutical ingredients and one or more pharmaceutically acceptableexcipients or heat sensitive polymers. In other embodiments, the activepharmaceutical ingredients and one or more pharmaceutically acceptableexcipients are added in a ratio of from about 1:2 to 1:9, respectively.In still other embodiments, the active pharmaceutical ingredients andone or more pharmaceutically acceptable heat sensitive polymers areadded in a ratio of from about 1:2 to 1:9, respectively. In certainembodiments, the second time period may be at least about five percent,10 percent, 15 percent, 20 percent, 25 percent or more of the first timeperiod. In other embodiments, the speed during the second time period isincreased by about 100 revolutions per minute (“RPM”), 200 RPM, 300 RPM,400 RPM, 500 RPM, 600 RPM, 700 RPM, 800 RPM, 900 RPM, 1000 RPM, 1100RPM, 1200 RPM, 1300 RPM, 1400 RPM, 1500 RPM, 1600 RPM, 1700 RPM, 1800RPM, 1900 RPM, 2000 RPM, 2100 RPM, 2200 RPM, 2300 RPM, 2400 RPM, 2500RPM, or more as compared to the speed during the first time period. Forexample, in one embodiment the first speed is greater than 1000 RPM andthe second speed is 200 to 400 RPM greater than the first speed. Inanother embodiment, the first speed is greater than 1000 RPM and thesecond speed is 200 to 1000 RPM greater than the first speed. In stillanother embodiment, the first speed is greater than 1000 RPM and thesecond speed is 200 to 2500 RPM greater than the first speed.

In one embodiment, the end of the first time period is substantiallybefore the mixing chamber temperature reaches the shear transitiontemperature or melting point of any substantial component of theingredients. In another embodiment, the end of the first time period isa predetermined time period and a change to the second speed is madeautomatically by the thermokinetic mixer at the end of the first timeperiod. In yet another embodiment, the end of the first time period issubstantially before the mixing chamber temperature reaches the sheartransition temperature of an active pharmaceutical ingredient in theingredients. In still another embodiment, the end of the first timeperiod is substantially before mixing chamber temperature reaches theshear transition temperature of an excipient in the ingredients. Inanother embodiment, the end of the first time period is substantiallybefore mixing chamber temperature reaches the shear transitiontemperature of a heat sensitive polymer in the ingredients.

In one embodiment, the end of the second or any subsequent time periodis substantially before an active pharmaceutical ingredient experiencessubstantial thermal degradation. In another embodiment, the end of thesecond or any subsequent time period is substantially before anexcipient ingredient experiences substantial thermal degradation. In yetanother embodiment, the end of the second or any subsequent time periodis substantially before a heat sensitive polymer ingredient experiencessubstantial thermal degradation. In one embodiment, at the end of thesecond or any subsequent time period the active pharmaceuticalingredient and an excipient of the ingredients are substantiallyamorphous. In another embodiment, at the end of the second or anysubsequent time period the active pharmaceutical ingredient and a heatsensitive polymer of the ingredients are substantially amorphous. Inother embodiments, upon achieving a final process parameter, the shaftrotation is stopped and a batch or composite is withdrawn or ejectedfrom the mixing chamber for further processing. In certain embodiments,the batch or composite is withdrawn or ejected at or below the glasstransition temperature of at least one of the components of the batch orcomposite. In other embodiments, the batch or composite is furtherprocessed by hot melt extrusion, melt granulation, compression molding,tablet compression, capsule filling, film-coating, or injection molding.In other embodiments, the batch or composite is withdrawn or ejected atthe beginning of a RPM plateau, for example before degradation occurs inthe batch or composite. In other embodiments, the RPM deceleration priorto withdrawal or ejection of the batch or composite is modulated toproduce a more uniform batch or composite.

Another embodiment of the present disclosure is directed to a method ofcompounding one or more active pharmaceutical ingredients and at leastone polymeric pharmaceutically acceptable excipient to produce anamorphous, homogenous, heterogenous, or heterogeneously homogenouscomposition, the method comprising thermokinetic mixing of the activepharmaceutical ingredient(s) and at least one polymeric pharmaceuticallyacceptable excipient in a chamber at a first speed effective to increasethe temperature of the mixture, and at a time point at which thetemperature is below the shear transition temperature of any activepharmaceutical ingredient or polymeric pharmaceutically acceptableexcipient in the mixture, increasing the mixer rotation to a secondspeed to produce an amorphous, homogenous, heterogenous, orheterogeneously homogenous composition, wherein the increase isaccomplished without stopping the mixing or opening the chamber. Inanother embodiment of the present disclosure, the method comprisesthermokinetic mixing in a chamber at one or more speeds effective toincrease the temperature of the mixture, at which time the shaft speedis adjusted to a different speed for a different time period, and at atime point at which the temperature is below the shear transitiontemperature of any active pharmaceutical ingredient or polymericpharmaceutically acceptable excipient in the mixture, and increasing themixer rotation to one or more different speeds, wherein the increase isaccomplished without stopping the mixing or opening the chamber.

Certain embodiments of the present disclosure are directed tothermokinetic mixers used to produce a pharmaceutical compositioncomprising one or more heat sensitive or thermolabile components.Various embodiments of the mixer may comprise one or more and anycombination of the following: (1) a mixing chamber, for example asubstantially cylindrical mixing chamber; (2) a shaft disposed throughthe center axis of the mixing chamber; (3) an electric motor connectedto the shaft, for example which is effective to impart rotational motionto the shaft; (4) one or more projections or extensions from the shaftand perpendicular to the long axis of the shaft; (5) one more heatsensors, for example attached to a wall of the mixing chamber andoperative to detect heat or temperature of at least a portion of theinterior of the mixing chamber; (6) a variable frequency device, forexample connected to the motor; (7) a door disposed in a wall of themixing chamber, for example which is effective when opened during aprocess run to allow the contents of the mixing chamber to pass out ofthe mixing chamber; and (8) an electronic controller. In certainembodiments, a hygroscopic condition is maintained within thethermokinetic mixer. In other embodiments, the thermokinetic mixers aredesigned to maximize shear during batch processing.

In certain embodiments, the electronic controller is in communicationwith the temperature sensors, the door and the variable frequencydevice. In some embodiments, the electronic controller comprises a userinput device, a timer, an electronic memory device configured to acceptuser input of process parameters or predetermined parameters for two ormore stages of a thermokinetic mixing processing, and a display. In anembodiment, the process parameters or predetermined parameters are savedin the memory device and displayed on the monitor for one or more stagesof a process run. In certain embodiments, when one of the predeterminedparameters is met during a stage of a processing run, the electroniccontroller automatically moves the process run to the subsequent stage.In other embodiments, the mixing chamber is interiorly lined by interiorliner pieces. The liner pieces may be made of material that minimizesany stickiness of the batch during processing, for example stainlesssteel and other such steel alloys, titanium alloys (such as nitrided ornitride-containing titanium), and wear and heat resistant polymers (suchas Teflon®).

In one embodiment of the present disclosure, at least one of thetemperature sensors detects infrared radiation, for example wherein theradiation level is output as temperature on the display. In otherembodiments, the predetermined parameters may be any one or acombination of the following: temperature, rate of temperature change,shaft rotational speed (e.g., rate of acceleration and deceleration),amperage draw of the electric motor, time of stage, or rate ofwithdrawal or exit of the batch or composite. One of skill in the artwill be able to change each of the following parameters to obtain abatch or composite with the desired characteristics through routineexperimentation. In another embodiment, the output display may be anyone or a combination of the following: chamber temperature, motorrevolutions per minute, amperage draw of the motor, or cycle elapsedtime.

In certain embodiments of the present disclosure, the one or moreprojections or extensions from the shaft comprise a base and an endportion, and, for example, the end portion may be removable from thebase portion and the base portion may be removable from the shaft. Inother embodiments, the projections or extensions are replaceable in thethermokinetic mixer, for example based on wear and tear or differentbatch parameters. In one embodiment, the one or more projections orextensions from the shaft comprise one or more main facial portionshaving a width of at least about 0.75 inches, at an angle of between 15to 80 degrees from a shaft axis plane. In other embodiments, the one ormore projections or extensions from the shaft comprise one or more mainfacial portions having a width of at least about 0.80 inches, 0.85inches, 0.90 inches, 0.95 inches, 1.0 inches, 1.1 inches, 1.2 inches,1.3 inches, 1.4 inches, 1.5 inches, 1.6 inches, 1.7 inches, 1.8 inches,1.9 inches, 2.0 inches, 2.1 inches, 2.2 inches, 2.3 inches, 2.4 inches,2.5 inches, 2.6 inches, 2.7 inches, 2.8 inches, 2.9 inches, 3.0 inches,3.1 inches, 3.2 inches, 3.3 inches, 3.4 inches, 3.5 inches, 3.6 inches,3.7 inches, 3.8 inches, 3.9 inches, 4.0 inches, 4.1 inches, 4.2 inches,4.3 inches, 4.4 inches, 4.5 inches, 4.6 inches, 4.7 inches, 4.8 inches,4.9 inches, 5.0 inches, or greater, at an angle of about 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 degrees from a shaft axisplane. In certain embodiment, the one or more projections or extensionsfrom the shaft control translation of rotational shaft energy deliveredto the projections or extensions into heating energy within particlesimpacting the projections.

In other embodiments, these dimensions of the one or more projections orextensions from the shaft are designed to increase the shear profile ofthe population of shear-resistant particles in the batch, for example toproduce substantially amorphous composites. In certain embodiments, thedimensions of the one or more projections or extensions from the shaftare designed to produce composites that are at least about 60, 65, 70,75, 80, 85, 90, 95, or 99 percent amorphous.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentdisclosure. The disclosure may be better understood by reference to oneor more of these drawings in combination with the detailed descriptionof specific embodiments presented herein.

FIG. 1. A view of the thermokinetic mixer assembly.

FIG. 2. An exploded view of the thermokinetic mixer.

FIG. 3. A shaft-radial cutaway view of a thermokinetic mixing chamber.

FIG. 4. An exploded view of the thermokinetic mixing chamber.

FIG. 5. Analysis of batch sensed temperature, shaft rotational speedingin RPMs, and amperage draw on the motor as a directly proportionalmeasure of energy input into the batch at any moment with one rotationalshaft speed.

FIG. 6. Analysis of batch sensed temperature, shaft rotational speedingin RPMs, and amperage draw on the motor as a directly proportionalmeasure of energy input into the batch at any moment with two rotationalshaft speeds.

FIG. 7. A graph block diagram of a thermokinetic mixer process at two ormore rotational shaft speeds.

FIG. 8. A cross section of a main facial portion of a prior art shaftextension.

FIG. 9. A cross section of a main facial portion of a shaft extensionwith a shaft axial plane at an angle of about 15 degrees.

FIG. 10. A cross section of a main facial portion of a shaft extensionwith a shaft axial plane at an angle of about 30 degrees.

FIG. 11. A cross section of a main facial portion of a shaft extensionwith a shaft axial plane at an angle of about 45 degrees.

FIG. 12. A cross section of a main facial portion of a shaft extensionwith a shaft axial plane at an angle of about 60 degrees.

FIG. 13. An alternative design of a cross section of a main facialportion of a shaft extension.

FIG. 14. An alternative design of a cross section of a main facialportion of a shaft extension.

FIG. 15. An alternative design of a cross section of a main facialportion of a shaft extension.

FIG. 16. An alternative design of a cross section of a main facialportion of a shaft extension.

FIG. 17. An alternative design of a cross section of a main facialportion of a shaft extension.

FIG. 18. An alternative design of a cross section of a main facialportion of a shaft extension.

FIG. 19. An exploded view of the thermokinetic mixer showing internalliner pieces.

FIG. 20. A generalized side view of a shaft extension's top faceinteraction with an inside surface of a mixing chamber.

FIG. 21. A perspective view of a shaft extension with variable top facepath lengths.

FIG. 22. An alternative design of a front face of a shaft extension.

DETAILED DESCRIPTION OF THE INVENTION

Although making and using various embodiments of the present disclosureare discussed in detail below, it should be appreciated that the presentdisclosure provides many inventive concepts that may be embodied in awide variety of contexts. The specific aspects and embodiments discussedherein are merely illustrative of ways to make and use the disclosure,and do not limit the scope of the disclosure.

To facilitate the understanding of this disclosure, a number of termsare defined below. Terms defined herein have meanings as commonlyunderstood by a person of ordinary skill in the areas relevant to thepresent disclosure. Terms such as “a”, “an” and “the” are not intendedto refer to only a singular entity, but include the general class ofwhich a specific example may be used for illustration. With regard tothe values or ranges recited herein, the term “about” is intended tocapture variations above and below the stated number that may achievesubstantially the same results as the stated number. In the presentdisclosure, each of the variously stated ranges is intended to becontinuous so as to include each numerical parameter between the statedminimum and maximum value of each range. For Example, a range of about 1to about 4 includes about 1, 1, about 2, 2, about 3, 3, about 4, and 4.The terminology herein is used to describe specific embodiments of thedisclosure, but their usage does not delimit the disclosure, except asoutlined in the claims.

As used herein, the term “thermokinetic compounding” or “TKC” refers toa method of thermokinetic mixing until melt blended. TKC may also bedescribed as a thermokinetic mixing process in which processing ends ata point sometime prior to agglomeration.

As used herein, the term “main facial portion” refers to the “top face”of a shaft extension. The top face of a shaft extension is the facefacing the inside wall of the mixing chamber of a thermokinetic mixer.

As used herein, the term “shear transition temperature” refers to thepoint at which further energy input does not result in an immediate risein temperature.

As used herein, the phrase “a homogenous, heterogenous, orheterogeneously homogenous composite or an amorphous composite” refersto the various compositions that can be made using the TKC method.

As used herein, the term “heterogeneously homogeneous composition”refers to a material composition having at least two different materialsthat are evenly and uniformly distributed throughout the volume.

As used herein, “bioavailability” is a term meaning the degree to whicha drug becomes available to the target tissue after being administeredto the body. Poor bioavailability is a significant problem encounteredin the development of pharmaceutical compositions, particularly thosecontaining an active ingredient that is not highly soluble. In certainembodiments such as formulations of proteins, the proteins may be watersoluble, poorly soluble, not highly soluble, or not soluble. The skilledartisan will recognize that various methodologies may be used toincrease the solubility of proteins, e.g., use of different solvents,excipients, carriers, formation of fusion proteins, targetedmanipulation of the amino acid sequence, glycosylation, lipidation,degradation, combination with one or more salts and the addition ofvarious salts.

As used herein, the phrase “pharmaceutically acceptable” refers tomolecular entities, compositions, materials, excipients, carriers, andthe like that do not produce an allergic or similar untoward reactionwhen administered to humans in general.

As used herein, the term “active pharmaceutical ingredient” or “API” isinterchangeable with the terms “drug,” “drug product,” “medication,”“liquid,” “biologic,” or “active ingredient.” As used herein, an “API”is any component intended to furnish pharmacological activity or otherdirect effect in the diagnosis, cure, mitigation, treatment, orprevention of disease, or to affect the structure or any function of thebody of humans or other animals. In certain embodiments, the aqueoussolubility of the API may be poorly soluble.

Examples of APIs that may be utilized in the present disclosure include,but are not limited to, antibiotics, analgesics, vaccines,anticonvulsants, anti-diabetic agents, anti-fungal agents,anti-neoplastic agents, anti-parkinsonian agents, anti-rheumatic agents,appetite suppressants, biological response modifiers, cardiovascularagents, central nervous system stimulants, contraceptive agents, dietarysupplements, vitamins, minerals, lipids, saccharides, metals, aminoacids (and precursors), nucleic acids and precursors, contrast agents,diagnostic agents, dopamine receptor agonists, erectile dysfunctionagents, fertility agents, gastrointestinal agents, hormones,immunomodulators, anti-hypercalcemia agents, mast cell stabilizers,muscle relaxants, nutritional agents, ophthalmic agents, osteoporosisagents, psychotherapeutic agents, parasympathomimetic agents,parasympatholytic agents, respiratory agents, sedative hypnotic agents,skin and mucous membrane agents, smoking cessation agents, steroids,sympatholytic agents, urinary tract agents, uterine relaxants, vaginalagents, vasodilator, anti-hypertensive, hyperthyroids,anti-hyperthyroids, anti-asthmatics and vertigo agents. In certainembodiments, the API is a poorly water-soluble drug or a drug with ahigh melting point.

The API may be found in the form of one or more pharmaceuticallyacceptable salts, esters, derivatives, analogs, prodrugs, and solvatesthereof. As used herein, a “pharmaceutically acceptable salt” isunderstood to mean a compound formed by the interaction of an acid and abase, the hydrogen atoms of the acid being replaced by the positive ionof the base. Non-limiting examples of pharmaceutically acceptable saltsinclude sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate. Another method for defining the ionic salts may be as anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Non-limitingexamples of bases include, but are not limited to, hydroxides of alkalimetals such as sodium, potassium and lithium; hydroxides of calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia; and organic amines, such as unsubstituted or hydroxysubstituted mono-, di-, or trialkylamines; dicyclohexylamine;tributylamine; pyridine; N-methyl-N-ethylamine; diethylamine;triethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl amines), suchas mono- bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

A variety of administration routes are available for delivering the APIsto a patient in need. The particular route selected will depend upon theparticular drug selected, the weight and age of the patient, and thedosage required for therapeutic effect. The pharmaceutical compositionsmay conveniently be presented in unit dosage form. The APIs suitable foruse in accordance with the present disclosure, and theirpharmaceutically acceptable salts, derivatives, analogs, prodrugs, andsolvates thereof, can be administered alone, but will generally beadministered in admixture with a suitable pharmaceutical excipient,diluent, or carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice.

The APIs may be used in a variety of application modalities, includingoral delivery as tablets, capsules or suspensions; pulmonary and nasaldelivery; topical delivery as emulsions, ointments or creams;transdermal delivery; and parenteral delivery as suspensions,microemulsions or depot. As used herein, the term “parenteral” includessubcutaneous, intravenous, intramuscular, or infusion routes ofadministration.

The excipients and adjuvants that may be used in the presently disclosedcompositions and composites, while potentially having some activity intheir own right, for example, antioxidants, are generally defined forthis application as compounds that enhance the efficiency and/orefficacy of the active ingredients. It is also possible to have morethan one active ingredient in a given solution, so that the particlesformed contain more than one active ingredient.

As stated, excipients and adjuvants may be used to enhance the efficacyand efficiency of the APIs. Non-limiting examples of compounds that canbe included are binders, cryoprotectants, lyoprotectants, surfactants,fillers, stabilizers, polymers, protease inhibitors, antioxidants andabsorption enhancers. The excipients may be chosen to modify theintended function of the active ingredient by improving flow, orbioavailability, or to control or delay the release of the API. Specificnonlimiting examples include: sucrose, trehaolose, Span 80, Tween 80,Brij 35, Brij 98, Pluronic, sucroester 7, sucroester 11, sucroester 15,sodium lauryl sulfate, oleic acid, laureth-9, laureth-8, lauric acid,vitamin E TPGS, Gelucire 50/13, Gelucire 53/10, Labrafil, dipalmitoylphosphadityl choline, glycolic acid and salts, deoxycholic acid andsalts, sodium fusidate, cyclodextrins, polyethylene glycols, labrasol,polyvinyl alcohols, polyvinyl pyrrolidones and tyloxapol. Using theprocess of the present disclosure, the morphology of the activeingredients can be modified, resulting in highly porous microparticlesand nanoparticles.

Exemplary thermal binders that may be used in the presently disclosedcompositions and composites include but are not limited to polyethyleneoxide; polypropylene oxide; polyvinylpyrrolidone;polyvinylpyrrolidone-co-vinylacetate; acrylate and methacrylatecopolymers; polyethylene; polycaprolactone;polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose;hydroxyalkylcelluloses such as hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, andhydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropyl methylcellulose; starches, pectins;polysaccharides such as tragacanth, gum arabic, guar gum, and xanthangum. One embodiment of the binder is poly(ethylene oxide) (PEO), whichcan be purchased commercially from companies such as the Dow ChemicalCompany, which markets PEO under the POLY OX™ trademark exemplary gradesof which can include WSR N80 having an average molecular weight of about200,000; 1,000,000; and 2,000,000.

Suitable grades of PEO can also be characterized by viscosity ofsolutions containing fixed concentrations of PEO, such as for example:

Viscosity Range POLYOX Aqueous Solution Water-Soluble Resin NF at 25°C., mPa · s POLYOX Water-Soluble Resin NF    30-50 (5% WSR N-10solution) POLYOX Water-Soluble Resin NF    55-90 (5% WSR N-80 solution)POLYOX Water-Soluble Resin NF   600-1,200 (5% WSR N-750 solution) POLYOXWater-Soluble Resin NF 4,500-8,800 (5% WSR-205 solution) POLYOXWater-Soluble Resin NF 8,800-17,600 WSR-1105 (5% solution) POLYOXWater-Soluble Resin NF   400-800 (2% WSR N-12K solution) POLYOXWater-Soluble Resin NF 2,000-4,000 (2% WSR N-60K solution) POLYOXWater-Soluble Resin NF 1,650-5,500 (1% WSR-301 solution) POLYOXWater-Soluble Resin NF 5,500-7,500 (1% WSR Coagulant solution) POLYOXWater-Soluble Resin NF 7,500-10,000 WSR-303 (1% solution)

Suitable thermal binders that may or may not require a plasticizerinclude, for example, Eudragit™ RS PO, Eudragit™ S100, Kollidon SR(poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer), Ethocel™(ethylcellulose), HPC (hydroxypropylcellulose), cellulose acetatebutyrate, poly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG),poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose(HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethylmethacrylate-methacrylic acid ester copolymer,ethylacrylate-methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50(Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), celluloseacetate trimelletate (CAT), poly(vinyl acetate) phthalate (PVAP),hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylateethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylatemethylmethacrylate) (1:1) copolymer (MA-MMA), poly(methacrylatemethylmethacrylate) (1:2) copolymer, Eudragit L-30-D™ (MA-EA, 1:1),Eudragit L-100-55™ (MA-EA, 1:1), hydroxypropylmethylcellulose acetatesuccinate (HPMCAS), Coateric™ (PVAP), Aquateric™ (CAP), and AQUACOAT™(HPMCAS), polycaprolactone, starches, pectins; polysaccharides such astragacanth, gum arabic, guar gum, and xanthan gum.

The stabilizing and non-solubilizing carrier may also contain variousfunctional excipients, such as: hydrophilic polymer, antioxidant,super-disintegrant, surfactant including amphiphillic molecules, wettingagent, stabilizing agent, retardant, similar functional excipient, orcombination thereof, and plasticizers including citrate esters,polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, andothers known to those or ordinary skill in the art. Extruded materialmay also include an acidifying agent, adsorbent, alkalizing agent,buffering agent, colorant, flavorant, sweetening agent, diluent,opaquant, complexing agent, fragrance, preservative or a combinationthereof.

Exemplary hydrophilic polymers which can be a primary or secondarypolymeric carrier that can be included in the composites or compositiondisclosed herein include poly(vinyl alcohol) (PVA),polyethylene-polypropylene glycol (e.g. POLOXAMER™), carbomer,polycarbophil, or chitosan. Hydrophilic polymers for use with thepresent disclosure may also include one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, methylcellulose, natural gums such as gum guar,gum acacia, gum tragacanth, or gum xanthan, and povidone. Hydrophilicpolymers also include polyethylene oxide, sodium carboxymethycellulose,hydroxyethyl methyl cellulose, hydroxymethyl cellulose,carboxypolymethylene, polyethylene glycol, alginic acid, gelatin,polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides,polymethacrylamides, polyphosphazines, polyoxazolidines,poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer,ammonium alginate, sodium alginate, or mixtures thereof.

By “immediate release” is meant a release of an active agent to anenvironment over a period of seconds to no more than about 30 minutesonce release has begun and release begins within no more than about 2minutes after administration. An immediate release does not exhibit asignificant delay in the release of drug.

By “rapid release” is meant a release of an active agent to anenvironment over a period of 1-59 minutes or 0.1 minute to three hoursonce release has begun and release can begin within a few minutes afteradministration or after expiration of a delay period (lag time) afteradministration.

As used herein, the term “extended release” profile assumes thedefinition as widely recognized in the art of pharmaceutical sciences.An extended release dosage form will release the drug (i.e., the activeagent or API) at a substantially constant rate over an extended periodof time or a substantially constant amount of drug will be releasedincrementally over an extended period of time. An extended releasetablet generally effects at least a two-fold reduction in dosingfrequency as compared to the drug presented in a conventional dosageform (e.g., a solution or rapid releasing conventional solid dosageforms).

By “controlled release” is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, 16hours, 18 hours, 20 hours, a day, or more than a day. By “sustainedrelease” is meant an extended release of an active agent to maintain aconstant drug level in the blood or target tissue of a subject to whichthe device is administered.

The term “controlled release”, as regards to drug release, includes theterms “extended release”, “prolonged release”, “sustained release”, or“slow release”, as these terms are used in the pharmaceutical sciences.A controlled release can begin within a few minutes after administrationor after expiration of a delay period (lag time) after administration.

A slow release dosage form is one that provides a slow rate of releaseof drug so that drug is released slowly and approximately continuouslyover a period of 3 hr, 6 hr, 12 hr, 18 hr, a day, 2 or more days, aweek, or 2 or more weeks, for example.

The term “mixed release” as used herein refers to a pharmaceutical agentthat includes two or more release profiles for one or more activepharmaceutical ingredients. For example, the mixed release may includean immediate release and an extended release portion, each of which maybe the same API or each may be a different API.

A timed release dosage form is one that begins to release drug after apredetermined period of time as measured from the moment of initialexposure to the environment of use.

A targeted release dosage form generally refers to an oral dosage formthat is designed to deliver drug to a particular portion of thegastrointestinal tract of a subject. An exemplary targeted dosage formis an enteric dosage form that delivers a drug into the middle to lowerintestinal tract but not into the stomach or mouth of the subject. Othertargeted dosage forms can deliver to other sections of thegastrointestinal tract such as the stomach, jejunum, ileum, duodenum,cecum, large intestine, small intestine, colon, or rectum.

By “delayed release” is meant that initial release of drug occurs afterexpiration of an approximate delay (or lag) period. For example, ifrelease of drug from an extended release composition is delayed twohours, then release of the drug begins at about two hours afteradministration of the composition, or dosage form, to a subject. Ingeneral, a delayed release is opposite of an immediate release, whereinrelease of drug begins after no more than a few minutes afteradministration. Accordingly, the drug release profile from a particularcomposition can be a delayed-extended release or a delayed-rapidrelease. A “delayed-extended” release profile is one wherein extendedrelease of drug begins after expiration of an initial delay period. A“delayed-rapid” release profile is one wherein rapid release of drugbegins after expiration of an initial delay period.

A pulsatile release dosage form is one that provides pulses of highactive ingredient concentration, interspersed with low concentrationtroughs. A pulsatile profile containing two peaks may be described as“bimodal.” A pulsatile profile of more than two peaks may be describedas multi-modal.

A pseudo-first order release profile is one that approximates a firstorder release profile. A first order release profile characterizes therelease profile of a dosage form that releases a constant percentage ofan initial drug charge per unit time.

A pseudo-zero order release profile is one that approximates azero-order release profile. A zero-order release profile characterizesthe release profile of a dosage form that releases a constant amount ofdrug per unit time.

The resulting composites or compositions disclosed herein may also beformulated to exhibit enhanced dissolution rate of a formulated poorlywater soluble drug.

An example of a composition or formulation having a stable releaseprofile follows. Two tablets having the same formulation are made. Thefirst tablet is stored for one day under a first set of conditions, andthe second tablet is stored for four months under the same first set ofconditions. The release profile of the first tablet is determined afterthe single day of storage and the release profile of the second tabletis determined after the four months of storage. If the release profileof the first tablet is approximately the same as the release profile ofthe second tablet, then the tablet/film formulation is considered tohave a stable release profile.

Another example of a composition or formulation having a stable releaseprofile follows. Tablets A and B, each comprising a compositionaccording to the present disclosure, are made, and Tablets C and D, eachcomprising a composition not according to the present disclosure, aremade. Tablets A and C are each stored for one day under a first set ofconditions, and tablets B and D are each stored for three months underthe same first set of conditions. The release profile for each oftablets A and C is determined after the single day of storage anddesignated release profiles A and C, respectively. The release profilefor each of tablet B and D is determined after the three months ofstorage and designated release profiles B and D, respectively. Thedifferences between release profiles A and B are quantified as are thedifferences between release profiles C and D. If the difference betweenthe release profiles A and

B is less than the difference between release profiles C and D, tabletsA and B are understood to provide a stable or more stable releaseprofile.

Specifically, the TKC process can be used for one or more of thefollowing pharmaceutical applications.

Dispersion of one or more APIs, wherein the API is a small organicmolecule, protein, peptide, or polynucleic acid; in polymeric and/ornon-polymeric pharmaceutically acceptable materials for the purpose ofdelivering the API to a patient via oral, pulmonary, parenteral,vaginal, rectal, urethral, transdermal, or topical routes of delivery.

Dispersion of one or more APIs, wherein the API is a small organicmolecule, protein, peptide, or polynucleic acid; in polymeric and/ornon-polymeric pharmaceutically acceptable materials for the purpose ofimproving the oral delivery of the API by improving the bioavailabilityof the API, extending the release of the API, targeting the release ofthe API to specific sites of the gastrointestinal tract, delaying therelease of the API, or producing pulsatile release systems for the API.

Dispersion of one or more APIs, wherein the API is a small organicmolecule, protein, peptide, or polynucleic acid; in polymeric and/ornon-polymeric pharmaceutically acceptable materials for the purpose ofcreating bioerodable, biodegradable, or controlled release implantdelivery devices.

Producing solid dispersions of thermolabile APIs by processing at lowtemperatures for very brief durations.

Producing solid dispersions of APIs in thermolabile polymers andexcipients by processing at low temperatures for very brief durations.

Rendering a small organic API amorphous while dispersing in a polymeric,non-polymeric, or combination excipient carrier system.

Dry milling of crystalline API to reduce the particle size of the bulkmaterial.

Wet milling of crystalline API with a pharmaceutically acceptablesolvent to reduce the particle size of the bulk material.

Melt milling of a crystalline API with one or more molten pharmaceuticalexcipients having limited miscibility with the crystalline API to reducethe particle size of the bulk material.

Milling crystalline API in the presence of polymeric or non-polymericexcipient to create ordered mixtures where fine drug particles adhere tothe surface of excipient particles and/or excipient particles adhere tothe surface of fine drug particles.

Producing heterogeneously homogenous composites or amorphous compositesof two or more pharmaceutical excipients for post-processing, e.g.,milling and sieving, which are subsequently utilized in secondarypharmaceutical operations well known to those of skill in the art, e.g.,film coating, tableting, wet granulation and dry granulation, rollercompaction, hot melt extrusion, melt granulation, compression molding,capsule filling, and injection molding.

Producing single phase, miscible composites of two or morepharmaceutical materials previously considered to be immiscible forutilization in a secondary processing step, e.g. melt extrusion, filmcoating, tableting and granulation.

Pre-plasticizing polymeric materials for subsequent use in film coatingor melt extrusion operations.

Rendering a crystalline or semi-crystalline pharmaceutical polymeramorphous, which can be used as a carrier for an API in which theamorphous character improves the dissolution rate of the API-polymercomposite, the stability of the API-polymer composite, and/or themiscibility of the API and the polymer.

Deaggregate and disperse engineered particles in a polymeric carrierwithout altering the properties of the engineered particles.

Simple blending of an API in powder form with one or more pharmaceuticalexcipients.

Producing composites comprising one or more high melting point APIs andone or more thermolabile polymers without the use of processing agents.

Homogenously dispersing a coloring agent or opacifying agent within apolymer carrier or excipient blend.

In the following detailed description of preferred embodiments of thepresent disclosure, reference is made to the figures in the drawings, inwhich the same numeral refers to an identical or similar part indifferent figures.

The present disclosure is directed to a novel thermokinetic mixer andmixing process that can blend heat sensitive or thermolabile componentswithout substantial thermal degradation. In particular, the disclosureis useful in processing mixtures that include thermolabile componentswhose exposure to a melt temperature or a cumulative heat input over adefined time period results in degradation. One embodiment of presentdisclosure is directed to a method for a continuous melt blend of anautoheated mixture in the mixing chamber of a high speed thermokineticmixer, where a first speed is changed mid-process to a second speed uponachieving a first desired or predetermined process parameter. In otherembodiments, the second speed is changed mid-process to a third speedupon achieving a second desired or predetermined process parameter.Additional speed changes are also within the scope of the presentdisclosure, as dictated by the number of desired or predeterminedprocessing parameters needed to produce the desired composition orcomposite.

This process is especially applicable for producing solid dispersions ofthermolabile APIs by processing at low temperatures for very briefdurations at multiple speeds, producing solid dispersions of APIs inthermolabile polymers and excipients by processing at low temperaturesfor very brief durations at multiple speeds, producing solid dispersionsof APIs in thermolabile excipients by processing at low temperatures forvery brief durations at multiple speeds, and producing solid dispersionsof heat sensitive polymers by processing at low temperatures forrelatively brief durations at multiple speeds.

One embodiment is to use two or more different speeds duringthermokinetic processing of a batch to reduce required processing timeafter a shear transition temperature of a portion of the batch isreached. Another embodiment is to use two or more different speedsduring thermokinetic processing of a batch to reduce required processingtime where the batch reaches a temperature whereafter a substantialamount of heat generated by frictional contact with shaft extensionsand/or an inside surface of the mixing chamber produces thermaldegradation of one or more components of the batch, and reducing thespeed. Yet a further embodiment is to use two or more different speedsduring thermokinetic processing of a batch to reduce required processingtime where the batch reaches a temperature whereafter a substantialamount of heat generated by frictional contact with shaft extensionsand/or an inside surface of the mixing chamber does not result in anoverall temperature increase for the batch. Yet a further embodiment isto provide a thermokinetic processing method using two speeds to reducethermal degradation of thermolabile or heat sensitive polymers orcomponents of a batch processed thereby.

In one embodiment, at least a portion of a batch in the mixing chamberof the high speed mixer comprises heat sensitive or thermolabilecomponents whose exposure to a limit temperature or limit of cumulativeheat input over a defined time period must be substantially prevented orlimited to obtain a melt blended batch with acceptable degradation ofthe heat sensitive or thermolabile components. In this embodiment, atleast one of the speed changes between a start and end of the process ismade so that the limit temperature or limit of heat input is notexceeded, thereby preserving the heat sensitive or thermolabilecomponents in the composition or composite.

Thermolabile components include, but are not limited to, thermolabileAPIs, excipients or polymers. Heat sensitive polymers include, but arenot limited to, nylon, polytrimethylene terephthalate, polybutene-1,polybutylene terephthalate, polyethylene terephthalate, polyolefins suchas polypropylene and high-density or low-density polyethylene, andmixtures or copolymers thereof, which polymers can be subject to surfaceand bulk polymer deficiencies as well as extrusion limitations. Otherheat sensitive polymers include poly (methylmethacrylate), polyacetal,polyionomer, EVA copolymer, cellulose acetate, hard polyvinylchlorideand polystyrene or copolymers thereof. A limit temperature in thedisclosed process for such heat sensitive polymers may be chosen bymaintaining sensed temperature of a batch within an acceptable rangefrom the well known degradation temperature for that polymer, such asabout 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, or 100 degrees Celsius from a temperature at which it is known inthe art that heat sensitive polymers begin to undergo degradation of adesired process parameter.

One embodiment of the present disclosure is a method for continuousblending and melting of an autoheated mixture in the mixing chamber of ahigh speed mixer, where a first speed is changed mid-processing to asecond speed upon achieving a first desired or predetermined processparameter. In one embodiment, the second speed is maintained until afinal desired or predetermined process parameter is achieved, whereuponshaft rotation is stopped and a melt blended batch is withdrawn orejected from the mixing chamber for further processing. The shaftoperates at one or more intermediate rotational speeds between changingto the second speed and stopping the shaft rotation. Process parameterswhich determine shaft speed changes are predetermined and may be sensedand displayed, calculated, inferred, or otherwise established withreasonable certainty so that the speed change(s) is made during asingle, rotationally continuous processing of a batch in a mixingchamber of the high speed mixer. Process parameters include withoutlimitation temperature, motor RPM, amperage draw, and time.

This disclosure is also directed to a thermokinetic mixer that can blendheat sensitive or thermolabile components without substantial thermaldegradation. One embodiment of the thermokinetic mixer has a highhorsepower motor driving the rotation of a horizontal shaft withteeth-like protrusions that extend outward normal to the rotational axisof the shaft. The shaft is connected to a drive motor. The portion ofthe shaft containing the protrusions is contained within an enclosedvessel where the compounding operation takes place, i.e., athermokinetic mixing chamber. The high rotational velocity of the shaftcoupled with the design of the shaft protrusions imparts kinetic energyonto the materials being processed. A temperature sensor senses thetemperature within the thermokinetic mixing chamber. Once a settemperature is sensed, a first speed is changed to a second speed.

FIG. 1 shows a view of one embodiment of the disclosed thermokineticmixer assembly. A temperature sensor 20 is connected to a thermokineticmixing chamber MC. The temperature sensor 20 provides information to aprogrammable logic controller 20 a which appears on a programmable logiccontroller display 20 b. A drive motor 15 controls the speed of theshaft which rotates through the mixing chamber MC.

The drive motor 15 is controlled by a variable frequency drive 20 c. Thevariable frequency drive 20 c also provides information to theprogrammable logic controller 20 a which appears on the programmablelogic controller display 20 b. When a desired process parameter is met,the programmable logic controller 20 a signals the variable frequencydrive 20 c to change the frequency of the electrical power supplied tothe drive motor 15. The drive motor 15 changes the shaft speed of theshaft. The temperature sensor 20 can be a sensor to radiation emittedfrom batch components.

FIG. 2 shows an exploded view of one embodiment of the thermokineticmixer. A frame 1 supports associated components such that a shaftassembly 2 is inserted in an axis of a shaft hole through end plate 3and a feed screw hole through end plate 4, the two end plates definingenclosing ends of a mixing chamber cylinder, the bottom portion of thecylinder defined by the inside surface of the lower housing 5. Lowerhousing 5 comprises a dropout opening closed off during operation withdischarge door 6. The upper housing 7 comprises an upper part of thecylinder of the inside surface of the mixing chamber. The feed housing 8is adapted to permit feeding of material to the feed screw of the shaftassembly so that such material is, in combination with the feed screwrotation, compressingly forced into mixing chamber from an externalfeed. Door 6 rotatably closes about discharge door pivot pin 9. Endplate 3 has attached to it a rack & pinion cylinder 18 with spacer 10interposed. At the top of housing 7 is mounted a bracket 11 with whichto support an infrared temperature sensor 20 for the mixing chamber.Door guard 12 protects the sometimes high temperature door 6 fromaccidental human contact with dropout material. Rotary guard 13 anddrive coupling guard 14 guard human operators from contact with rotatingcomponents during operation. Drive motor 15 is preferably an electricmotor with sufficient power to accomplish the disclosed operation. Thepillow blocks 16 and 17 support the shaft assembly 2.

In an example of a system in which the process parameters that determineshaft speed changes are measured in the mixing chamber and/or drivemotor, FIG. 7 shows a block flow diagram of the disclosed process wherea mixing chamber MC is connected by a shaft to a drive motor 42, where avariable frequency drive 41 controls the rotational speed of drive motor42. In certain embodiments, shaft speed can be from 0 through 5000 RPM.Further, a programmable logic controller 40 determines and carries out achange in rotational shaft speed using a variable frequency drive 41according to the disclosed process. The programmable logic controller 40comprises setpoints entered by a user for determination of a need forchanging a rotational shaft speed in drive motor 42 and to transmit tothe variable frequency drive 41 a command to change such speed afterrotational processing of the batch load has been added to the mixingchamber. The programmable logic controller may incorporate amicroprocessor comprising memory incorporating a control program adaptedto act upon achievement of setpoints entered by a user relying on sensordata transmitted from drive motor 42 and/or mixing chamber MC, andinclude a user interface such as a programmable logic controller displayfor a user to observe operating time and/or sensor data transmitted fromdrive motor 42 and/or mixing chamber MC. The programmable logiccontroller optionally comprises a method for a user to directly changemotor shaft speeds upon consideration of predetermined processparameters (such as operation time) or upon comparison of predeterminedprocess parameters with sensor data transmitted from drive motor 42and/or mixing chamber MC (such as batch temperature, amperage draw, andshaft speed). The programmable logic controller optionally comprises anautomated control method to change motor shaft speeds uponmicroprocessor operation at predetermined, stored process parameters(such as operation time) or upon comparison of predetermined, storedprocess parameters with sensor data transmitted from drive motor 42and/or mixing chamber MC (such as batch temperature, amperage draw andshaft speed).

A description of components of one embodiment of a thermokinetic mixerfor the disclosed process is shown in FIGS. 3 and 4. FIG. 3 shows ashaft-radial cutaway view of a mixing chamber MC for a thermokineticmixer of the disclosure with halves 5 and 7 joined to form a cylindricalmixing cavity having shaft 23 rotating in rotation direction 24 in anaxial length of the chamber. Shaft extensions 30 extend from theirreleasable connection on shaft 23 to a position near an inside surface19. Shaft extension 30 comprises top face 22 and front face 21.Particles 26 a-26 e show impingement of such particles on shaftextension 30 and on inside surface 27, which impingement causescomminution and/or frictional heating of the particles by the sheargenerated by such impingement. Further, FIG. 4 is an exploded view ofthe extensions and mixing chamber shown in FIG. 3, where shaftextensions 30 a, 30 b, and 30 c each having a top face 22 and a frontface 21 defined upon a replaceable tooth which is adapted to be securedto foot section 31 by bolt 33. Section 31 is adapted to be replaceablyfixed to shaft 23 (continued from motor shaft 37) at slot 35 by way ofbottom section 32 of section 31. FIG. 4 shows that particles aregenerally moving in direction 38 when they encounter shaft extensions 30a to 30 c. Shaft extension 30 a is shown having its front face 21aligned effectively opposing those of shaft extensions 30 b and 30 c.

With a typical batch process, a user will first select two components,which could include, for example, a thermolabile API and a polymerexcipient. The user will then empirically determine the shear transitiontemperatures of the two components. The user will then set the processparameters (temperature, RPM, amperage draw, and time) in theprogrammable logic controller to change from the first speed to thesecond speed as is suitable for the shear transition temperatures of thecomponents. Any of the setpoints entered by the user can be used as astop point following the period of the second speed.

FIG. 5 shows certain potential differences between the methods of thepresent disclosure, and that of a thermokinetic mixing method using asubstantially single shaft speed. FIG. 5 shows a graph of batch sensedtemperature, shaft rotational speed in RPMs, and amperage draw on themotor as a directly proportional measure of energy input into the batchat any moment in the processing. As a specific example the followingcomposition was thermokinetically processed to form a batch ofGriseofulvin:PVP (1:2 ratio) at a batch size of 60 grams. Griseofulvinrepresents a thermolabile API. PVP represents an excipient. A series ofthree tests is represented in FIG. 5 and was conducted in athermokinetic mixer similar in construction to that shown in FIGS. 3 and4, where front faces 21 project in a forward rotation direction with aside to side width of about 1.0 inches and are maintained at about 30degrees away from a plane extending from an axis of the shaft 23 througha leading edge of the front faces 21 with a height of about 2.5 inches.The batch in FIG. 5 was processed under thermokinetic, autoheatingconditions in which a substantially single shaft speed was used. They-axis is applicable to temperature (values times 10) and shaft speed inRPM (value times 30). Time on the x-axis is in increments of 0.10seconds. If the composition of this batch were thermokinetically mixedat rotational shaft speeds substantially higher than that shown in FIG.5, i.e., at 2500 RPM and higher, inspection of the final product showedthat it was unacceptably crystalline and insufficiently amorphous. Thisresult would be unexpected to one of skill in the art. Higher shaftspeeds are taught in the thermokinetic mixing art to assure bettermixing, which did not occur at higher shaft speeds with these materials.When the example batch composition was processed as shown in FIG. 5, atlower rotational shaft speed, inspection of the final product showedthat it was sufficiently amorphous and adequate for bioavailability.However, unacceptable thermal degradation of the thermolabile APIoccurred, which rendered the batch unacceptable.

In FIG. 5, at time zero, amperage draw immediately increased to 35 amps(1050 on the graph). Ejection of the batch was at about 17.6 seconds orwhere RPMs are shown to dramatically decline. The rotational shaft speedwas set for 1800 RPMs and reached that speed within about 2 seconds fromstart. Within about 7 seconds, the batch temperature reached 260° F.,the shear transition temperature for the excipient. Above the sheartransition temperature, the excipient's resistance to shear dramaticallydecreased and energy delivered to the batch by impingement of particlesand molten material on the extension surfaces and inside surface of themixing chamber consequently also dramatically decreased (the amperagedraw dropped to about one half when the shear transition temperature wasreached in the batch temperature). From about 7 seconds to 16 seconds,the batch temperature of the composition was not rising whilesubstantial energy continued to be absorbed by the batch. Such energythat did not result in increased temperature translated to thermaldegradation of the thermolabile or heat sensitive components. This testconfirms in general that once a significant amount of a component, i.e.,greater than 5 weight percent, 10 weight percent, 20 weight percent, or30 weight percent, in a thermokinetically melt blended batch reaches itsshear transition temperature or melting point, a substantial amount ofheat absorbed by the entire batch results in thermal degradation ofthermolabile or heat sensitive components instead of increasing overallbatch temperature. This is clearly shown in the time range from 7through 16 seconds in FIG. 5, where batch temperature actually decreasedwith continuous energy input to the batch.

The same batch and thermokinetic mixer in FIG. 5 were used in FIG. 6,but two speeds were implemented through the continuous rotational batchprocessing. In FIG. 6, a programmable logic controller connected to aninfrared sensor and a variable frequency drive was used for detecting abatch temperature, comparing the batch temperature to a predeterminedsetpoint, and automatically changing rotational shaft speed of thethermokinetic mixer to another speed for the duration of the processuntil the batch was released by way of opening a bottom dropout door. Afirst speed was set for 1800 RPM and a second speed was set for 2600RPM. The predetermined setpoint for the batch temperature was chosen tobe 200° F. as a substantial level below the excipient shear transitiontemperature. It is critical to effect a speed change before asubstantial component's shear transition temperature is reached, and thesystem requires response time between the moment a sensed batchtemperature is transmitted to the programmable logic controller and theshaft speed actually is changed. As shown in FIG. 6, no substantialenergy input to the batch was diverted from overall batch temperatureincrease. The processed batch showed substantially complete amorphosityand no detectable thermal degradation of the API with an overallprocessing time of about 6.5 seconds. This time stands in dramaticcontrast to that of the processing time of that in FIG. 5 at 17.6seconds.

FIG. 6 indicates that shaft rotational speed for certain thermolabilecomponents should be substantially increased at or before a substantialcomponent or portion of a thermokinetically batch reaches a sheartransition temperature or melting point, whereafter processing timeshould be minimized. In certain embodiments, a first speed should beincreased by about 100 RPM, 200 RPM, 300 RPM, 400 RPM, 500 RPM, 600 RPM,700 RPM, 800 RPM, 900 RPM, 1000 RPM, or more to a second speed. In otherembodiments, a processing time after the second speed starts until thebatch is released from the mixing chamber should be about 5 percent, 10percent, 15 percent, 20 percent, 25 percent or more of the total timethe batch was processed at the first speed.

It is well known in the art that impact of a particle on a surfaceimparts energy to the particle. It is a feature of thermokinetic,auto-heating mixers to provide impact on a particle containing polymerswhereby imparted energy is translated partly into heat energy to softenand/or melt those polymers. However, the thermokinetic mixing artgenerally directs those skilled in the art to provide impact forparticles in thermokinetic mixers in a manner that lacks fine control oftranslation of impact energy into heat energy. The present disclosureprovides for and describes methods for such control. Highly cross-linkedpolymers and thermoset compounds are highly refractory to softening andmelting for the same reason they are preferred, i.e., they resistbreaking down. Yet, they are shown to be of value in some combinationsof components processed with thermokinetic mixing. Indeed, thermokineticmixing is essentially the only way to process highly cross-linkedpolymers and thermosets due to their resistance to melting and blendingin any other manner. In the thermokinetic mixing art, increasingrotational shaft speed and/or processing time were understood to be themethod by which melt-resistant polymers could be induced to translatesufficient impact energy to heat energy to effect a softened or moltenstate for further processing. The present embodiment discloses anapparatus and methods by which impact energy translation to heat energycan be effectively controlled.

Two primary impact surfaces, the front face and the top face of a shaft,control impact translation to heat energy in a thermokinetic mixer.Those two surfaces are the facial portions of the shaft extensions thatintrude into the outer 30 percent or less of volume of the mixingchamber (the volume is referred to hereafter as the “main processingvolume”; it includes a most restricted zone of about one inch inwardradius from the inside cylindrical wall of the mixing chamber) and theinside cylindrical surface of the mixing chamber itself. Changing theinside cylindrical surface of the mixing chamber is not a practicaloption—that surface, being stationary, must remain smooth andcylindrically uniform to resist buildup of molten materials and to allowfor skidding and sliding autoheating contact with particles being movedthrough the mixing chamber.

The present disclosure uses variations in the top face of the shaftextensions that intrude into the main processing volume to controltranslation of rotational shaft energy delivered to the extensions intoheating energy within particles impacting the portions. It has beenfound that varying the width and angle away from a shaft axis plane forthe main facial portion provides a controllable variation in sheardelivered to a particle impacting the portion, which in turn providescontrol over shaft energy translated into heat energy available forsoftening or melting a polymer part of a particle in a thermokineticmixing chamber.

Referring again to FIGS. 3 and 4, it has been found that providingparticles within the mixing chamber a cumulative experienced shear whichis determined by the shape and dimensions of a rotation-directed facialsurface of extensions from the shaft and the inside surfaces of themixing chamber results in the autoheating phenomena of thermokineticmixing. Substantially all the particles within a mixing chamber duringshaft rotation inhabit the outer 30 percent of the volume of theinternal space, i.e., the centrifugal force of the rotation of theextensions maintains the particulates and molten materials away from acentral volume of the mixing chamber. Thus, the effective thermokineticmixer must be designed so that distal end parts of the shaft extensionsare formed to accomplish the three functions of direct high shear (onthe end part front face of the extension), indirect high shear (on theinside surfaces of the mixing chamber), and centrifugal maintenance ofmaterial in the outer volume of the mixing chamber. The top faces ofshaft extensions 30 a to 30 c form a substantially vertical rectanglearranged at an angle away from a plane passing through an axis of shaft23. It has been found that changing the width, angle, or varying theshape of the simple rectangle or arcuate paddle of the shaft provides anunexpected improvement and control over cumulative shear delivered toparticles within a mixing chamber of a thermokinetic mixer, which, inturn, provides control over imparted heat energy and desired heat inputto heat sensitive or thermolabile components in a processed batch.

For these specific comparisons of the operation of thermokinetic mixerswith several configurations of a main facial portion, it is assumed thatenergy input through the shaft and the shaft rotational speed is aboutthe same and that the number of shaft extensions and their spacing alongthe length of the shaft within the mixing chamber is substantially thesame. Thus, the comparisons will show the effect of changing the shapesof the main facial portion.

In general, decreasing the width relative to the length of the mainfacial portion increases shaft energy translated into heat energyavailable for softening or melting a polymer part of a particle in athermokinetic mixing chamber. The width must be above a minimum contactwidth so that a particle experiences a sliding impact along the width,the particle is induced into a “skid” or energy imparting frictionalcontact, rolling and sliding at the period of time for impact on theportion. Mere normal glancing impact of a particle on a surface isrelatively ineffective in imparting thermokinetic, autoheating energyfor softening or melting. Yet, easily melted and heat-labile or heatsensitive polymers in some cases are sometimes processed with a mainfacial portion providing just such glancing impact to provide morecontrol over heat application to such components. Consistent with thisteaching, polymers refractory or resistant to softening or melting byapplication of heat are often processed with a main facial portion ofminimum width (at least 0.25 inches) aligned at a minimum angle backfrom a shaft axial plane (for example, at least 10 degrees or at least15 degrees) providing a contact time for essentially the same energyinput, whereby distribution of that energy into skidding and rotationalmotion improves autoheating of the particle's polymer content.

A design of a shaft extension currently found in the Draiswerke Gelimat®thermokinetic mixer has the cross section 50 shown in FIG. 8, having arounded main facial portion 51 and an overall substantially spiral shapewith a width of about 2 inches.

Relative shear 52 shown in a number of shortened arrows directed at themain facial portion 51 is not substantial for this design. Thus, thisdevice has been relatively costly in terms of increased processing timeand shaft power to generate sufficient thermokinetic heating tomelt-blend polymers with substantial resistance to softening or melting.As such, it is relatively inadequate for processing heat labile or heatsensitive polymers having such resistance. There has been no suggestionin the thermokinetic mixing art that changing the width or angle of themain facial portion relative to a shaft axial plane would have anyaffect on thermokinetic processing of polymers. The present disclosurediscloses such embodiments in FIGS. 9 through 12.

FIGS. 9 through 12 respectively show main facial portion cross sections53 through 56 having main facial portions 57 through 60 with identicalwidths at angles of about 15 degrees, 30 degrees, 45 degrees and 60degrees back from a shaft axial plane for the extensions which theyrepresent. The projected widths on that shaft axial plane of main facialportions 57 through 60 are shown respectively in lengths 65 through 68and are directly related to relative shears 61 through 64, where anincreasing angle of a main facial portion relative to a shaft axialplane with identical width decreases the projected width onto the planeand unexpectedly increases relative shear for the same shaft powerinput, rotational shaft speed and extension spacing and arrangement onthe shaft. With this disclosure, it is now possible to controlautoheating by delivered shear in the extensions of a thermokineticmixer. Decreasing the widths of main facial portions while maintainingthe angle relative to a shaft axial plane maintains total heat inputinto a thermokinetically processed batch in the mixers but increasesshear upon any individual particle by reducing projected length alongthe shaft axial plane.

Thus, the shear strength of polymers processed by way of thermokinetic,autoheating mixing and blending can now be matched to the relative shearenergy imparted by the shaft extensions in the mixing chamber. A furtherdesign refinement is desirable where, as is quite common, polymercomponents in a batch comprise both high shear and low shear polymers.Providing a main facial portion suited for a high shear componentimparts shear energy which may deliver too much heat energy to low shearcomponents. In such a case, the low shear component tends to soften androll along the width of the main facial portion, further increasing theheat generated, while the high shear components tend to leave thatsurface more readily. Such a circumstance could tend to cause incompletemixing with the high shear components insufficiently melted oroverheating of low shear components. There is yet a further need fordesigns of a main facial portion that achieve an optimal shear deliveryto high and low shear components in a thermokinetic batch.

It has been found that increasing the width of the main facial portionachieves this optimization. At an angle of between 15 to 80 degrees froma shaft axis plane, and the main facial portion having a width of atleast 0.75 inches, provides sufficient path travel for both high and lowshear polymer components in a batch so that the high shear componentsremain in sliding and skidding contact with the main facial portion longenough to generate heat and absorb heat from lower shear components tobecome softened and thereby blend with the low shear components.

Alternate designs for the main facial portion are shown in FIGS. 13through 17, respectively, showing main facial portion cross sections 69,72, 76, 80, 84, and 87. FIG. 13 shows cross section 69 comprising aleading acute surface 70 extending rearward to obtuse surface 71,providing a first low shear surface followed by a higher shear surface.FIG. 14 shows cross section 72 comprising a leading acute surface 73extending rearward to 90 degree surface 74, which in turn extendsrearward to tailing acute surface 75, providing a first low shearsurface followed by a higher shear surface and a lower shear surface.FIG. 15 shows cross section 76 comprising a leading acute surface 77extending rearward to obtuse surface 78, which in turn extends rearwardto tailing acute surface 79, providing a first low shear surfacefollowed by a higher shear surface and a lower shear surface. FIG. 16shows cross section 80 comprising a leading obtuse surface 73 extendingrearward to acute surface 74, which in turn extends rearward to tailingobtuse surface 75, providing a first high shear surface followed by alower shear surface and a high shear surface. FIG. 17 shows crosssection 84 comprising a leading and rising arcuate surface 85 extendingrearward to a tailing and reducing arcuate surface 86 degree surface 74,which in turn extends rearward to tailing acute surface 75, providing afirst low shear surface followed by a higher shear surface and a lowershear surface. FIG. 18 shows cross section 87 comprising a leading acutesurface 88 and a tailing acute surface 89, providing a first low shearsurface followed by a higher or lower shear surface, depending on theshear of the batch components.

In light of the above teaching of these embodiments, the top face 22 ofFIG. 4 is a significant element in providing thermokinetic contact withparticles in the mixing chamber and causing them to impact the insidecylindrical surface of the mixer.

FIG. 19 shows another significant embodiment of the thermokinetic mixerof the present disclosure, in that halves 5 and 7 and door 6 arerespectively interiorly lined by interior liner pieces 5 a, 7 a and 6 a.The liner pieces are adapted to intimately lie adjacent to insidesurfaces of halves 5 and 7 and door 6 during operation of the mixer,thereby providing any of a diverse set of thermokinetic frictionalcontact surfaces desired for accelerated particles, such desiredsurfaces selected from among any appropriate or optimized materials forliner pieces 5 a, 7 a and 6 a. FIG. 19 shows in exploded view the linerpieces 5 a, 7 a and 6 a separated from their adjacent (as installed)parts. Bolting the halves 5 and 7 together cause liner pieces 5 a and 7a to secure to line the inside surfaces of those halves 5 and 7. Holesin end sections of liner piece 6 a allows for bolted connection of it todoor 6. In thermokinetic mixers known to those of skill in the art, theinside surfaces of the mixing chamber were limited to those steel alloyswith sufficient mechanical and thermal strength required for encasingand enclosing the thermokinetic operation of such mixers. Therefore,known thermokinetic mixers were limited in their processing capabilitiesto only those mixtures which would not excessively adhere to a smoothinside surface of steel alloy of the mixing chamber and which, at thesame time, would impinge beneficially on those surfaces to providefrictional heating of particles in the mixture. Further, even relativelyslight wear on the inside surfaces of the mixing chambers ofthermokinetic mixers can dramatically alter the efficacy of thegeneration of thermokinetic heating of chambered particles, in that thedistance between the shaft extensions and the inside surface of themixing chamber is specifically designed to optimize thermokineticheating by the interaction of particles moving between the insidesurface of the mixing chamber and the shaft extensions. Thus, suchslight wear can require that the entire, relatively expensive set ofhalves 5 and 7 to be replaced in such thermokinetic mixers. The presentembodiment eliminates such excessive cost. Liner pieces 5 a, 7 a and 6 aare relatively much less in cost to replace than halves 5 and 7 and door6. Replacement of the liner pieces is quite simple and fast. Preferredliner piece composition includes stainless steel (alloys with greaterthan 12 weight percent chrome) and other such steel alloys, titaniumalloys (such as nitrided or nitride-containing titanium), and wear andheat resistant polymers (such as Teflon®). It is another embodiment ofthe present disclosure to provide non-smooth inside surfaces for linerpieces 5 a, 7 a and 6 a, such as parallel or spiral grooving about theinside cylindrical surfaces of liner pieces 5 a, 7 a and 6 a, surfacetexturing, and/or electropolishing. Such materials and texturing forliner pieces 5 a, 7 a and 6 a are intended to obtain an optimum ordesirable balance of characteristics which will reduce undesirableadhesion of thermokinetically melted particles and/or promotethermokinetic frictional contact of mixing chamber particles in theirtravel among the shaft extensions and the inside surfaces of the linerpieces 5 a, 7 a and 6 a.

In a further embodiment of the present disclosure whereby materials ortexturing of liner pieces 5 a, 7 a and 6 a are selected to obtain theobjects of thermokinetic mixing, shaft extension portions comprising thefront and top impact faces of the shaft extensions are adapted by way ofmaterial composition and/or texturing similar to those changes justdisclosed for the inside surfaces of liner pieces 5 a, 7 a and 6 a.

Another feature of the present disclosure is that the top face of theshaft extensions, i.e., those which extend at least with a slightelevation rearward above the height of the front face of the shaftextension to form a ramp structure upon which chambered particlesimpinge (faces 22 of FIGS. 3 and 4), are the primary location of wearamong the inside surfaces of the mixing chamber. The consequences ofthis discovery are considerable with respect to the design of shaftextensions in thermokinetic mixers. It has been found that such a topface has a function very different than that of the front face. A frontface of a shaft extension drags a particle along its rearward directedwidth, causing the particle to be driven substantially in a direction ofan axis of the drive shaft. Such an axis-driven particle will then tendto engage yet another front face of a shaft extension of a rearward andnext line of shaft extensions. The motion of particles in contact with atop face of a shaft extension driven by shaft rotation is verydifferent, imparting in such motion a substantially greater frictional,thermokinetic energy to a particle than the front face of the shaftextension.

FIG. 20 shows a side view (a view in the direction of the axis of ashaft to which it is mounted) of a removable portion of a shaftextension 30 showing a front face 21 and top face 22. Referenceelevations 30 b to 30 d are measured from a base level 30 a. Neitherfront face 21 or top face 22 are shown in plan view but rather are shownwith their projections upon the side shaft-axial view. Top face 22comprises a front edge rising from elevation 30 c to 30 b and thereaftersweeping rearward and upward to similarly inclined rear edge with ahighest elevation 30 d. Only a part of the inside surface of half 7 isshown as separated from top face 22 and portions P1 to P4 represent thepath of a particle impinging first upon top face 22 and then upon theinside surface of half 7. It has been found that the area of greatestwear on any inside surface of the mixing chamber is along the rearwardarea from the front edge represented by the line from elevations 30 c to30 b, i.e., the impact point of a particle at portion P1. A majorportion of kinetic energy is clearly translated to frictional heating tothe particle in that area as evidenced by the substantial wear on suchhardened surfaces. Top face 22 rises more rapidly at its far edge alongelevations 30 b to 30 d than along the near edge starting at elevation30 c, resulting in a relatively long frictional travel path of theparticle along portion P2 and being ramp-launched from elevation 30 dtoward the inside surface of half 7. Upon frictional, spinning, anddragging contact with the inside surface of half 7 at portion P3, theextensively heated particle rebounds from the inside surface of half 7to again contact a top face of another shaft extension. The length ofportion P2 substantially controls required frictional heating time forthermokinetic mixing and melting for a batch of particles within themixing chamber of the present disclosure. The present disclosurecomprises selecting a shaft extension which provides to an impingingparticle in thermokinetic mixing a top face contact path of longer orshorter length and angle of deflection to thereby control a substantialor majority of frictional heating contact of chambered particles to adesired batch temperature.

FIG. 21 shows a perspective view of a specific embodiment of the shaftextension of FIG. 20 having a concave front face 21 and a top face 22capable of producing variable lengths of portions P2′ (longer) and P2″(shorter) respectively for portions P3′ and P3″. In certain embodiments,the top face 22 comprise a convex surface with a radius of about 4.5inches extending from its front, leading edge to its rearmost edge.

In certain embodiments, a shaft extension providing a relatively longfrictional contact path for particles being processed by the mixer ofthe present disclosure are preferred for providing shortened processingtimes, i.e., to heat a batch to a desired temperature as quickly aspossible. Such control of heating and processing times is directlyapplicable to the disclosed process of two step continuous thermokineticmixing, whereby increasing rotational shaft speed will more swiftlyimpart frictional heating for melting energy to the particles morerefractory or resistant to lower speed heating. It has been found thatnon-uniformity of materials in a batch processed thermokinetically,i.e., either by composition or particle size, results in greater orlesser frictional path contact with the insides of the mixing chamber.Particles more resistant to melting, either by way of higher meltingtemperatures or hardness, will rebound more quickly from frictionalcontact with the inside surfaces of a thermokinetic mixer and therebyrequire more processing time than less refractory particles.Thermokinetic mixing to a final, desired processing consistency for heatlabile or heat damageable components generally favors reaching a targetbatch temperature as quickly as possible. Certain embodiments of thepresent disclosure provide short, medium, long or mixed lengths ofparticle frictional contact paths along a top face of a shaft extension,either by way of a single or multiple processing shaft speeds, toachieve the more effective mixing of certain thermolabile components.

It is well known to those in the art that the topmost surfaces of shaftextensions in the Draiswerke mixers are merely arcuately tapered andsmoothed ends of a generally sinous shaft extension. As such, theability of such mixers to provide substantial top face shearing,frictional heating to thermokinetic mixing chamber particles isessentially minimized. To accomplish additional top face-like frictionalpaths for particles in the mixing chamber and to accomplish otherobjects of the present disclosure, FIG. 22 discloses a frontal view ofan OPEN 30 shaft extension having a central OPENING so that particlescan pass through it during processing and impinging on identicallyrearwardly angled pairs of surfaces A1/A2, B1/B2 and C1/C2. It will beappreciated that surfaces A1/A2 together act upon particles as a topface and that surfaces B1/B2 and C1/C2 act upon particles as frontfaces. FIG. 22 more generally discloses that shaft extensions may beformed in a donut or toroid shape or in the shape of a diamond with acentral opening to accomplish the more effective mixing of certainthermolabile components.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of thisdisclosure have been described in terms of preferred embodiments, itwill be apparent to those of skill in the art that variations may beapplied to the compositions and/or methods and in the steps or in thesequence of steps of the method described herein without departing fromthe concept, spirit and scope of the disclosure. All such similarsubstitutes and modifications apparent to those skilled in the art aredeemed to be within the spirit, scope and concept of the disclosure asdefined by the appended claims.

It is to be understood that while certain forms of the present inventionhave been illustrated and described herein, it is not to be limited tothe specific forms or arrangement of parts described and shown.

What is claimed is:
 1. A thermokinetic mixer using replaceable impactface teeth with variable forward angles relative to an axis of a shaftcomprising: (a) a substantially cylindrical mixing chamber with aninside surface enclosing part of the shaft rotatable by an externaldrive motor at relatively high speed substantially about the axis of thecylindrical mixing chamber, the mixing chamber being adapted to receiveand release batches of particles of polymers and other material therein;(b) shaft extensions arranged in three or more rows, where each shaftextension is arranged radially to the shaft and each row is alignedlongitudinally to the shaft; (c) each shaft extensions having a forwardaligned tooth face and each tooth face is adapted to encounter particlesand drive them at least in part to the inside surface such thatsubstantial energy is imparted to them, generating thermokinetic heatingthereby; (d) each shaft extension is adapted to have a replaceable toothface so that the angle of the tooth face relative to an axis of theshaft may be increased or decreased by replacing the tooth faces toprovide, respectively, less or more impact energy to particles duringthermokinetic processing.
 2. The thermokinetic mixer of claim 1 whereinthe angle of first tooth faces relative to an axis of the shaft may isabout 15 degrees.
 3. The thermokinetic mixer of claim 2 wherein firsttooth faces are replaced with second tooth faces and the angle of secondtooth faces relative to an axis of the shaft may is about 30 degrees. 4.The thermokinetic mixer of claim 3 wherein second tooth faces arereplaced with first tooth faces and the angle of third tooth facesrelative to an axis of the shaft may is about 45 degrees.
 5. Thethermokinetic mixer of claim 4 wherein third tooth faces are replacedwith fourth tooth faces and the angle of fourth tooth faces relative toan axis of the shaft may is about 60 degrees.